STUDY DESIGN:A matched-pair study on the relationship between proliferation associated markers Ki-67, PCNA, and p53 and treatment failure in carcinomas of the oropharynx and oral cavity.MATERIAL AND METHOD:Fifty-six T1-T3 carcinomas of the oropharynx or oral cavity, treated uniformly with primary surgery and postoperative irradiation, were investigated. Twenty-eight patients had recurrent disease and were matched with 28 patients with nonrecurrent disease regarding stage and location of tumor as well as age and therapy. MIB1 staining was used to determine the Ki-67 labeling index. Immunohistochemical studies determined the p53 status and PCNA labeling index.RESULTS:Where treatment failed, the Ki-67 labeling index was significantly (p = 0.032) higher (mean = 59.1%) than in patients without recurrence (mean = 50.5%). Mean time to relapse was 45 months (n = 25) for carcinomas with a Ki-67 (MIB1) labeling index above the median (53.7%) of the general study population, compared to 61.7 months for those cases (n = 31) below this median (p = 0.029). The PCNA labeling index did not correlate significantly with tumor recurrence, nor with time to relapse. In 46% of all tumors, p53 overexpression was present. No significant correlation could be found between p53 overexpression and tumor recurrence or time to relapse.CONCLUSION:Examination of Ki-67 is thought to provide useful prognostic information concerning squamous cell carcinomas of the oropharynx and oral cavity. Overexpression of p53 or PCNA status is not of prognostic value, which is consistent with earlier results. We conclude that the detection of Ki-67 is an unfavorable prognostic factor for squamous cell carcinoma of the oropharynx and oral cavity, at least if treated with a combination of surgery and postoperative irradiation.

Squamous cell carcinomas of the head and neck from 50 untreated patients were analyzed for rearranged or amplified proto-oncogenes by Southern blot hybridization. The bcl-1 and hst genes were coamplified 8- to 32-fold in 5 of 46 patients (11%) and the c-erb A1 and c-erb B2 genes 32-fold in 1 of 46 patients (2%). Eight to 16-fold amplification of c-myc was observed in 4 of 46 tumor samples (8%), while 4-fold amplification of Ha-ras was found in 2 of 46 tumor samples (4%). There was one patient with a 64-fold c-erb B2 amplification without accompanying c-erb A1 amplification. RNA - expression analysis using Northern blot and poly-A-+ RNA techniques did not reveal any changes in the RNA expression of c-erb Al while c-erb B2, hst and bcl-1 were not expressed at all. No Ki-ras or N-myc amplification was observed, nor was any rearrangement of the above-mentioned oncogenes found. Clinical correlation existed between tumor stage and oncogene amplification: patients with stage I and II disease (IUCC,AJCC) showed no amplification at all, whereas 14 patients with stage III and IV disease showed amplified oncogenes (P = 0,015, chi2-test). In contrast, there was no correlation between oncogene amplification and disease development (observed over a minimum period of 3 years), nor could amplification be correlated with other clinical parameters (sex, tumor site, -histology) for any of the oncogenes. Present findings suggest that oncogene amplification in head and neck squamous cell carcinomas is a later acquired epiphenomenon of tumor progression but has no obvious clinical correlation at this time.

Squamous cell carcinomas of the head and neck from 50 untreated patients were analyzed for rearranged or amplified proto-oncogenes by Southern blot hybridization. The bcl-1 and hst genes were coamplified 8- to 32-fold in 5 of 46 patients (11%) and the c-erb A1 and c-erb B2 genes 32-fold in 1 of 46 patients (2%). Eight to 16-fold amplification of c-myc was observed in 4 of 46 tumor samples (8%), while 4-fold amplification of Ha-ras was found in 2 of 46 tumor samples (4%). There was one patient with a 64-fold c-erb B2 amplification without accompanying c-erb A1 amplification. RNA-expression analysis using Northern blot and poly-A-+RNA techniques did not reveal any changes in the RNA expression of c-erb A1 while c-erb B2, hst and bcl-1 were not expressed at all. No Ki-ras or N-myc amplification was observed, nor was any rearrangement of the above-mentioned oncogenes found. Clinical correlation existed between tumor stage and oncogene amplification: patients with stage I and II disease (IUCC,AJCC) showed no amplification at all, whereas 14 patients with stage III and IV disease showed amplified oncogenes (P = 0.015,chi 2-test). In contrast, there was no correlation between oncogene amplification and disease development (observed over a minimum period of 3 years), nor could amplification be correlated with other clinical parameters (sex, tumor site, -histology) for any of the oncogenes.(ABSTRACT TRUNCATED AT 250 WORDS)

Squamous cell carcinomas of the head and neck from 40 untreated patients were analysed for rearranged or amplified proto-oncogenes by Southern blot hybridisation. The bcl-1 and the hst genes were coamplified 8–32-fold in 5 patients (12.5%). Only males with stage III and IV disease showed coamplification of these oncogenes. Northern blot analysis of the positive samples did not show expression of bcl-1 or hst genes. In contrast, a third oncogene located on chromosome 11 (Ha-ras-1) was not amplified in these tumours. Disease development was observed in all cases over a minimum period of 3 years. Survival of the patients with coamplification of hst/bcl-1 seemed to be shorter than of those with stage III and IV disease without amplification. This difference was not significant probably due to the small number of investigated patients.

We have analysed DNA and RNA from 40 untreated head and neck cancers for amplified and overexpressed proto-oncogenes by Southern and Northern blot hybridisation. Coamplification but no expression of the bcl-1 and the hst genes was found in 12.5% of the patients. Furthermore, amplifications of c-myc were found in 10%, of Ha-ras and c-erbB-2 in 5%. c-erbB-2 amplification was accompanied by gene expression but no overexpression. Correlating our results with clinicopathological data of the patients amplifications were only found in stage III and IV disease (p=0.0164). No correlation was found between amplification and primary tumour site, histopathological differentiation of the tumours, response to induction chemotherapy, or survival. Our results indicate that oncogene amplification in advanced SCCHN reflects more the general genomic instability of advanced tumours than be a reason for tumour growth.

Qualitative und quantitative Veränderungen im genetischen Material einer Zelle können zu unkontrollierter Zellteilung und damit zur Tumorentstehung führen. Eine zentrale Rolle spielen dabei Veränderungen im Bereich sog. Onkogene, die normalerweise Zellteilung und -funktion kontrollieren.

Proto-oncogenes are a part of the genetic code of each human cell. Physiologically they code special enzymes, membrane receptors and growth factors which are necessary for cell growth and function. Alterations in these genes like amplification, rearrangements, mutations or chromosomal translocation appeared to be implicated in the induction of neoplasms. So these genes were called "oncogenes". Recent work has shown that increased expression of the c-myc oncogene in squamous cell carcinoma (SCC) of the head and neck is related to advanced SCC stages (TNM). We examined more than fourty human SCC of the head and neck with Southern blot analysis for c-myc amplification and rearrangement. Our preliminary results indicate that c-myc amplification is correlated with advanced tumour stages and highly aggressive tumour behaviour. Patients with c-myc amplification (15%) all show regional lymph node metastasis. No rearrangement has been seen. Further studies must confirm our results and examine whether c-myc amplification is correlated with the biological characteristics of SCC of the head and neck.

Proto-Onkogene sind Teil des genetischen Codes jeder Zelle des menschlichen Organismus. Physiologischerweise codieren diese Gene spezielle Wachstumsfaktoren, Enzyme, Membranrezeptoren und Zellkernproteine, die für eine geregelte Zellfunktion von entscheidender Bedeutung sind. Störungen im Bereich dieser Regulationsgene durch Mutationen, Genamplifikationen, Chromosomentranslokationen oder eine ungeregelte Genexpression scheinen bei der Tumorentstehung eine wichtige Rolle zu spielen und führten zu der Bezeichnung „Onkogene”. Neuere Untersuchungen deuten an, dass bestimmte Veränderungen im Bereich dieser Gene Hinweise auf das Wachstumsverhalten der jeweiligen Tumoren geben können. So zeigten auch unsere Untersuchungen, dass eine Amplifikation eines der bekanntesten Onkogene - c-myc - bei Plattenepithelkarzinomen im Kopf-Hals-Bereich mit einem fortgeschrittenen Tumorstadium zu korrelieren scheint. Sollten weitere Untersuchungen diese ersten Ergebnisse bestätigen, so eröffnet der Nachweis hochspezifischer genetischer Tumormerkmale eine Möglichkeit, prospektive Aussagen zum Wachstumsverhalten, Metastasierungsmuster, zur Rezidivgefahr und damit zur Prognose des jeweiligen Tumors zu treffen.